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PSILOCYBIN, an indoleamine hallucinogen, produces a psychosis-like syndrome in humans that resembles first episodes of schizophrenia. In healthy human volunteers, the psychotomimetic effects of psilocybin were blocked dose-dependently by the serotonin-2A antagonist ketanserin or the atypical antipsychotic risperidone, but were increased by the dopamine antagonist and typical antipsychotic haloperidol. These data are consistent with animal studies and provide the first evidence in humans that psilocybin-induced psychosis is due to serotonin-2A receptor activation, independently of dopamine stimulation. Thus, serotonin-2A overactivity may be involved in the pathophysiology of schizophrenia and serotonin-2A antagonism may contribute to therapeutic effects of antipsychotics.

2Department of Anesthesiology, University Hospital of Zürich, Zürich, Switzerland

3Corresponding Author: Franz X. Vollenweider

ACKNOWLEDGEMENTS: This study was supported in part by the Swiss National Science Foundation (32-040'900) and Janssen-Cilag, Switzerland. The authors especially thank Dr S. Park and Dr J. Püschel for kindly providing the delayed response task (DRT), and Professor M. Geyer, UCSD, for critical comments on the manuscript.